Dr. Flanagan subproject

According to the World Health Organization approximately 50 million people worldwide suffer from cognitive disorders. The incidence of dementia increases with age, especially for those over 65. CNS white matter lesions are also known to increase with age and to increase the risk of developing dementia. Vascular dementia (VD) is the second most common cause of cognitive abnormalities in the elderly behind Alzheimer’s disease (AD). VD has been associated with various cardiovascular maladies, which are thought to contribute to diffuse white matter disease leading to dementia. The underlying hypothesis of this proposal is that the impact of the cytotoxic environment created by disruptions to the CNS vasculature associated with aging and diverse cardiovascular disorders are particularly detrimental to oligodendrocyte viability and function. We posit that the heightened sensitivity to cellular stress that oligodendrocytes display due to their unique metabolic demands makes them particularly vulnerable to the changing extracellular environment that develops with advancing age and in response an altered cerebral circulation. The white matter abnormalities that occur as a consequence of oligodendrocyte perturbation are likely critical to the development of neurodegenerative, cognitive and behavioral changes. The goal of the current proposal is to a gain a mechanistic understanding of the impact of ageing and cerebrovascular abnormalities on oligodendrocytes, both in humans and in mouse models. Our focus will be on examining the role that intrinsic cytoprotective pathways play in the response of oligodendrocytes to the adverse cytotoxic environment created by these conditions. We will focus on three cytoprotective pathways: the integrated stress response (ISR) pathway is initiated by a variety of stresses including oxidative stress, hypoxia and inflammation; the nuclear factor erythroid 2-related factor 2 (NRF2) pathway is activated in response to oxidative stress; and the hypoxia-inducible factor 1 (HIF-1) pathway is the master transcriptional regulator of the cellular response to hypoxia. We will examine human postmortem samples from individuals with vascular dementia for activation of these pathways in oligodendrocyte lineage cells, and we will similarly assess their activation in ageing mice, which are known to display oligodendrocyte and myelin deficiencies. We will also examine a mouse model of heart failure with preserved ejection fraction (HFpEF) for oligodendrocyte and myelin abnormalities linked to ISR, NRF2 and HIF activation. HFpEF is a common cardiovascular abnormality associated with dementia. We will also use a genetic approach to further examine the response of these cytoprotective pathways to the adverse CNS environment created by ageing and cerebrovascular abnormalities. Together, these efforts will substantially increase our understanding of the response of oligodendrocytes to the cytotoxic CNS environment created by ageing and cerebrovascular dysfunction. A better appreciation of the contribution of myelinating glia dysfunction to the pathogenesis of dementia is essential to our understanding of this growing health concern and may serve as the basis for the design of neuroprotective therapeutic strategies.